Drug Substance Solid State Characterization · A thorough knowledge of an active pharmaceutical ingredient’s (API) solid state behavior is essential for reliable drug product manufacturing,

Drug Substance Solid State Characterization

IntroductionA thorough knowledge of an active pharmaceutical ingredient’s (API) solid state

behavior is essential for reliable drug product manufacturing, patent protection, and

formulation viability. This article discusses various aspects of the API in the solid state

which can impact pharmaceutical product development.

Solubility and PermeabilitySolubility and permeability dictate bioavailability and thus dosage form efficacy. The Biopharmaceutical Classification System (BCS) classifies compounds based

on potency, solubility and membrane permeability, providing a guide for

formulation development1. A first step in preformulation is to determine

the API’s pH solubility profile. For ionizable compounds, these results

establish the relationship between charge state and pH; the ionization

constant (pKa) allows prediction of a compound’s absorption and

distribution in vivo. Another useful property is the partition coefficient (log P), which describes drug partitioning between aqueous and

organic phase; this is commonly measured with chromatographic

methods. Knowledge of pKa value(s) and log P are critical to

understanding the ability of an ionized molecule to permeate

biological membranes2. The majority of drugs in development

and those recently launched are poorly water soluble; this

presents a particular challenge in designing an optimal

formulation3. Ways to improve solubility include chemical

modification of APIs (e.g., prodrugs), use of co-solvents or other excipients (surfactants, phospholipids, cyclodextrins

and other polymers), and manipulation of particle size/ morphology. For the latter, there has been a growing trend

to apply particle size reduction and to control particle morphology.Reduction of particle size, most commonly through (nano)-milling, increases specific surface area, leading to enhanced dissolution and

Furthermore, reliable methods are required to confirm the correct polymorphic form during API synthesis and

formulation. There are many techniques used, including

optical microscopy, XRD, differential scanning calorimetry

(DSC), Fourier Transform infrared (FTIR), near infrared (NIR), Raman, and solid-state nuclear magnetic resonance (ssNMR).

Hydrates/SolvatesIn addition to polymorphs, solvated or hydrated drug

crystal forms occur. Their crystal structure may or may not

be different from the anhydrous form, and they can be

stoichiometric or non-stoichiometric in composition. API hydrates (sometimes referred to as pseudopolymorphs)

can be isolated and identified through screening stud-ies using organic solvent-water mixtures, but may also form spontaneously in the presence of excess moisture.

Conversely, hydrates can lose water upon drying, leading

to physical form changes8. Measurement of API water

uptake/loss over the entire humidity range is essential, and should be supplemented by DSC, thermogravimet-ric analysis (TGA), and/or XRD; Raman, and NIR are well suited to monitor hydrate formation during processing,

such as in wet granulation. Hydrates with adequate

physical stability are suitable for development if the API

interactions with water are well understood and can be

controlled during formulation and storage.

Traditionally there has been less interest in developing

solvates due to safety and regulatory concerns. None-theless, a solvate may be considered for development

if it can meet essential solubility and bioavailability

requirements. For this reason, solvate screens are often conducted in parallel with other solid form screens, and

the resulting stable solvates are included in patent claims.

Similar to hydrates, solvation and desolvation behavior of

the API should be monitored with appropriate analytical

methods. Solvate drug products are relatively rare, but

are represented by several marketed products, including

warfarin sodium and atorvastatin calcium (Lipitor).

Co-crystalsUnlike solvates and hydrates, these materials are de-signed through crystal engineering, i.e., two crystalline

solids interact to form a new crystalline entity. The new

structure is stabilized through hydrogen bonding modes, which can be confirmed with various techniques (FTIR, DSC, XRD, X-ray crystallography)9. Co-crystals have generated considerable interest over the last decade for

improved homogeneity of the bulk material. Finally, selection of the API solid form can also significantly

Influence solubility and thus formulation performance.

SaltsAcid or base drugs can often be converted to salts, result-ing in solubility improvement4. Salt screening is generally

done in discovery to identify the best API form(s) for

development; the drug is exposed to counterions and

crystallization solvents under various conditions. Products are typically analyzed by powder X-ray diffraction (XRD) and/or Raman spectroscopy, to confirm “hits” for further study and scale-up. And while salts are a potential avenue to explore, the toxicology and salt stability have to be

considered and evaluated prior to moving forward. For formulation, the toxicology considerations depend on the

type of salt and the planned dose. As to the stability, the

salt integrity in the dosage form must be maintained to

avoid reconversion to the less soluble acid or base form.

Polymorphs Many APIs can exist in multiple crystal forms, i.e.,

chemically identical but physically distinct as solids.

There is also crystal habit, wherein a polymorph exhibits

an external shape, conferring distinct and possibly

desirable properties5. Early polymorph screening

identifies and selects the best forms(s) for further evaluation. The existence of drug polymorphs has

important implications for patent claims, formulation

strategies and bioavailability6. Screening involves

recrystallization of the drug from a variety of solvents

under different conditions. It is generally highly

desirable to identify and develop the most stable

polymorph, bypassing forms that are more soluble

but metastable. While the latter offer the promise of

better solubility, there are challenges in preventing

eventual crystallization to the more stable, less soluble form.

Realistically, it may be impossible to find all existing polymorphs at an early stage. This can result in later

complications, including patent litigation and lengthy

delays in development time. An extreme example of

“the polymorph problem” is the drug ritonavir, where late stage appearance of a new, more stable polymorph

compromised original product performance, causing

its withdrawal from the market7. In recent years, high

throughput screening has facilitated form selection

at the early stage. However, this does not replace the

need for more detailed investigations of form stability.

hygroscopicity, and amorphization (which may occur during milling or micronization) must also be investigat-ed. Furthermore, the stability characteristics of the solid drug influence how it is packaged and stored: desiccant to prevent moisture uptake, amber glass containers to

minimize light exposure, refrigeration/freezing to prevent heat-induced degradation, are all considerations, particu-larly during transport.

Formulation ConsiderationsDuring manufacture, an API is exposed to multiple

processes on its way to a finished product. In formula-tions, the drug is combined with a variety of excipients;

drug-excipient incompatibility can compromise physical and chemical stability of the API11. A well-known example of chemical incompatibility is the Maillard reaction,

where browning occurs due to interaction between

amine-containing drugs and reducing sugars such as lactose. Rational choice of excipients is thus critical

and should be supported through preformulation

experiments – frequently high-performance liquid

chromatography (HPLC) and DSC are employed for

such screening.

As raw materials, characteristics of the solid drug and

associated excipients (e.g., moisture content) may

adversely influence tableting processes such as

compression or granulation, leasing to physical defects,

dissolution problems, and even product failure.

Sensitivity of API and excipients to manufacturing

conditions should also be considered. Finally, increasingly complex dosage forms require an

understanding of how other components can affect

API behavior. For example, properties of polymers used in delivery devices (molecular weight, degree of

cross-linking, crystallinity) can have a significant effect on drug release.

Case Studies These studies describe some approaches to solid-state characterization and formulation of poorly soluble APIs.

Compound A

Along with the most stable but least soluble polymorph

(Form 1), a metastable polymorph (Form 2) was identified which increased the dissolution rate 3-fold. Form 2

was successfully scaled up and formulated as a tablet.

However, during stability studies, Form 2 tablets

quickly converted to Form 1 at elevated temperature/

their potential to improve API solubility while maintaining

acceptable stability.

As with other drug physical forms, co-crystals screening systems are available, allowing rapid optimization of conditions to produce the desired products. The ability

of compounds to form co-crystals will be significantly influenced by structural factors such as the type and

number of substituents. In addition, regulatory perspec-tive on co-crystals continues to evolve. To this end, the FDA issued revised draft guidance in 2016.

AmorphousAs stated above, there is increasing interest in the use of

non- crystalline (amorphous) API forms as drug sub-stance and product. There are many ways of preparing

amorphous materials, including hot melt extrusion and

spray drying10. And while amorphous drugs are attractive

for solubility enhancement, they are inherently unstable

and pose challenges for formulation due to chemical

reactivity and hygroscopicity. Understanding and pre-venting crystallization of amorphous solid formulations (e.g., through use of polymeric crystallization inhibitors) is key to their successful development. Detection and

quantification of crystalline content in an amorphous matrix requires appropriate methods; XRD is a common

technique, along with spectroscopic methods (FTIR, NIR, Raman, ssNMR), isothermal microcalorimetry, and DSC.

The glass transition temperature (Tg), which can be

measured by DSC, signifies conversion of amorphous to crystalline state, and is used to predict amorphous form

stability. In general, the Tg value of amorphous material

should be as high as possible to maintain adequate

physical stability, although molecular mobility aspects

can affect this caveat. It is important to note that Tg

decreases significantly in the presence of moisture, leading to crystallization. In some cases, this problem can be minimized by storage of the amorphous material at low humidity and/or by use of a desiccant.

Stability Besides solubility, physical and chemical stability of solid

drug forms must be adequately characterized. To accom-plish this, solids are subjected to stresses (heat, humidity,

light) and analyzed. Chemical stability evaluates a drug’s susceptibility to degradation (acid, base, oxidant), and is

investigated in solution as well as in solid-state, typically with chromatographic methods. From a physical form standpoint, the possibilities of unwanted crystallization,

conversion, as spectral characteristics of the acid and

sodium salt forms are quite different. In the finished

tablet product, XRD patterns were utilized to confirm

the absence of the acid, which is distinct from that

of the salt. A second approach to enhance solubility

involved injection molding. The resulting extrudates,

which contained acid API, polymer, and a plasticizer, improved bioavailability and maintained physical

stability. Raman spectroscopy confirmed stabilizing

interactions of the drug with the polymer in the

amorphous matrix.

ConclusionProperties of solid drugs impact all stages of drug

development, from synthesis to production of clinical and

commercial supplies. Appropriate analytical methods are

needed not only to generate information during form

screening, but also for troubleshooting unexpected

problems with solid drug substance and product.

high humidity conditions, Fig. 1. In summary, the

solubility advantage of the metastable form could not

overcome its physical instability.

A second approach to improve API solubility used spray

drying to prepare amorphous solid dispersions. Success

here was highly dependent on the polymeric excipient

used. Certain dispersions remained amorphous by XRD

and showed enhanced dissolution compared to the API

alone, but others were physically unstable, exhibiting

crystallization. Early screening of polymers for compatibil-ity with the API was thus critical for optimizing the amor-phous formulation.

Compound B

The starting API was a crystalline acid; one approach to

enhance solubility was conversion of the acid to an in situ

sodium salt during granulation by addition of sodium

hydroxide. An in-process FTIR test was used to confirm

2-theta

Intensity cps

Lubrizol Life Science

Figure 1: XRD overlay showing conversion of Form 2 tablets to Form 1 after one month storage. Bottom to top: Initial (T0); 30 °C/65% RH; 40 °C/75% RH; Form 1.

The information contained herein is believed to be reliable, but no representations, guarantees or warranties of any kind are made as to its accuracy, suitability for particular applications or the results to be obtained. The information often is based on laboratory work with small-scale equipment and does not necessarily indicate end-product per-formance or reproducibility. Formulations presented may not have been tested for stability and should be used only as a suggested starting point. Because of the variations in methods, conditions and equipment used commercially in processing these materials, no warranties or guarantees are made as to the suitability of the products for the applications disclosed. Full-scale testing and end-product performance are the responsibility of the user. Lubrizol Advanced Materials, Inc., shall not be liable for and the customer assumes all risk and liability for any use or handling of any material beyond Lubrizol Advanced Materials, Inc.’s direct control. The SELLER MAKES NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. Nothing con-tained herein is to be considered as permission, recommendation nor as an inducement to practice any patented invention without permission of the patent owner. Lubrizol Advanced Materials, Inc., is a wholly owned subsidiary of The Lubrizol Corporation.

©2019 The Lubrizol Corporation, all rights reserved. All marks are the property of The Lubrizol Corporation. The Lubrizol Corporation is a Berkshire Hathaway company.

HEALTH_RX_TB40_SOLIDSTATECHARACTERIZATION NO1620 OCT 2019

9911 Brecksville Road Cleveland, OH 44141-3201 USA

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